Beta-lactam antibiotics, which generally are penicillins and cephalosporins, have been widely used in the treatment of infections, primarily bacterial, in mammals such as man. Certain micro-organisms are believed to be resistant to these antibiotics because they produce various beta-lactamase enzymes which attack the beta-lactam ring of the antibiotic thereby rendering the drug ineffective.
In U.S. Pat. No. 4,287,181, Kellogg disclosed that various 6β-hydroxyalkylpenicillanic acids, including 6-β-hydroxymethylpenicillanic acid sulfone which is the beta-lactamase inhibitor used in the present invention, are potent beta-lactamase inhibitors. U.K. Patent Application GB2053220A, Metzger et al. and U.K. Patent Application GB2076812, by Schneider et al., likewise disclosed that 6-β-hydroxymethyl-penicillanic acid sulfone is a beta-lactamase inhibitor. However, the beta-lactamase inhibitor 6-β-hydroxymethyl-penicillanic acid sulfone is very poorly absorbed in vivo in rodents during preclinical studies when administered orally.
Kellogg, Metzger et al. and Schneider et al. also disclosed ester prodrugs of 6-β-hydroxymethyl-penicillanic acid sulfone, which readily hydrolyze in vivo, during preclinical studies, and which demonstrated better absorption in rodents than did the free acid.
However, many of these ester prodrugs could only be synthesized as oils or as solids that had low melting points whose usefulness in pharmaceutical formulations is more limited than would be a solid prodrug with a melting point suitable for tableting, milling or purification.
Furthermore, these ester prodrugs were typically not highly absorbed when orally administered. Thus, higher drug dosages would be required to be administered orally, to obtain a therapeutically effective plasma level of the beta-lactamase inhibitor 6-β-hydroxy-methylpenicillanic acid sulfone, than would be required for a more highly absorbed prodrug. In addition, oral administration of the less absorbed prodrugs may result in an increase in the incidence and severity of diarrhea experienced by the recipient as the unabsorbed prodrug may hydrolyze in the gastro-intestinal tract, to form the active drug, and, with any residual amoxicillin, selectively kill essential components of the normal microbial flora. Further, it is desirable that the process, for producing the desired prodrug, be relatively inexpensive.
Therefore, there is a need for a crystalline prodrug of the beta-lactamase inhibitor 6-β-hydroxymethylpenicillanic acid sulfone which has a high oral bioavailability, and more preferably is crystalline with a suitable melting point.